Process for synthesizing carbapenem side chain intermediates

ABSTRACT

A process for the synthesis of an N-(di-substituted phosphoryl)-trans-4-hydroxy-L-proline of the formula I: ##STR1## is disclosed, wherein R 1  and R 2  independently represent C 1-18  alkyl, phenyl or phenyl-substituted C 1-18  alkyl, or R 1  and R 2  are taken in combination to represent C 2-4  alkylidene or phenyl. Trans-4-hydroxy-L-proline is reacted with a di-(substituted) phosphite of the formula III: ##STR2## in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula I.

This application claims the benefit of provisional Ser. No. 60/028,966 filed on Oct. 10, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to a process of synthesizing compounds that are useful in the manufacture of carbapenem side chains. These carbapenem antibiotic compounds are effective in the treatment of infections caused by susceptible bacterial organisms.

In the past, the synthesis of appropriately substituted hydroxyprolines has been conducted in the presence of a mixture of carbon tetrachloride, an amine base, e. g., triethylamine, water and an inert organic cosolvent, e.g., ethanol. See, e.g., Synthesis, 1988: 444-448. This process is somewhat undesirable in that it uses excess amounts of reagents and it uses and generates chlorinated hydrocarbons. The present invention utilizes stoichiometric amounts of more economical reagents and generates little undesirable side products.

SUMMARY OF THE INVENTION

A process for the synthesis of an N-(di-substituted phosphoryl)-trans-4-hydroxy-L-proline of the formula I: ##STR3## wherein R¹ and R² independently represent C₁₋₁₈ alkyl, phenyl or phenyl-C₁₋₈ alkyl, or R¹ and R² are taken in combination to represent C₂₋₄ alkylidene or phenyl, is disclosed wherein trans-4-hydroxy-L-proline of the formula II: ##STR4## is reacted with a di-(substituted) phosphite of the formula III: ##STR5## in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, C₁₋₁₈ alkyl refers to straight and branched alkyl groups, including C₅₋₁₈ alkyl groups which can be cyclic or bicyclic.

Likewise, the values of R¹ and R² include phenyl, phenyl-substituted C₁₋₁₈ alkyl and C₂₋₄ alkylidene. Preferred values of R¹ and R² include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl, 2-ethylhexyl, decyl, lauryl and octadecyl. The preferred value of R¹ and R² taken in combination is ethylene or phenyl. The most preferred value of R¹ and R² is isopropyl.

The resulting compounds, III are useful in the synthesis of carbapenem antibiotics, such as the compounds that are described in U.S. Pat. No. 5,478,820 granted on Dec. 26, 1995, and incorporated herein by reference.

Generally, the reaction ingredients are combined slowly at a reduced temperature, e.g., about 0° to about 5° C. The pH can be maintained at about 9.0 by adding a suitable quantity of sodium hydroxide. In a preferred aspect of the invention, the pH of the reaction is maintained at about 9.0.

Sodium hypochlorite can be used in concentrations ranging from about 5% to about 20 weight %.

Upon completion of the reaction, the pH of the solution can be adjusted with acid, and the desired compound isolated. Typically a crystalline product can be obtained.

In a preferred embodiment of the invention, the process is as described above wherein R¹ and R² independently or in combination represent members selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl, 2-ethylhexyl, decyl, lauryl, octadecyl and ethylene.

In a preferred embodiment of the invention, the present process is as described above wherein R¹ and R² independently represent C₁₋₁₈ alkyl.

In another preferred embodiment of the invention, the process is as described above wherein R¹ and R² independently represent phenyl-substituted C₁₋₁₈ alkyl.

In another preferred embodiment of the invention, the process is as described above wherein R¹ and R² represent phenyl.

In another preferred embodiment of the invention, the process is as described above wherein R¹ and R² taken in combination represent C₂₋₄ alkylidene or phenyl.

In another preferred embodiment of the invention, the process is as described above wherein R¹ and R² taken in combination represent ethylene or phenyl.

In a more preferred embodiment of the invention, the process described herein relates to the synthesis of N-(diisopropyl phosphoryl)-trans-4-hydroxy-L-proline of the formula Ia: ##STR6## which comprises reacting trans-4-hydroxy-L-proline of the formula II: ##STR7## with diisopropyl phosphite of the formula IIIa: ##STR8## in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula Ia.

The invention is further illustrated with the following non-limiting example.

EXAMPLE ONE ##STR9##

A mixture of water (12 L) and trans-hydroxy proline (5 Kg) was cooled to 0°-5° C. The pH of the solution was adjusted to 9.0 with NaOH (25%) and diisopropylphosphite (7.0 kg) was added.

Sodium hypochlorite (12.5 wt % NaOCl) (20 L) was added while maintaining the pH at 9.0 by the addition of sodium hydroxide.

After completion, the reaction was quenched with sodium bisulfite (750 g.) over 15 minutes. The pH of the solution was adjusted from neutrality to approximately 2 by the addition of conc. HCl at 0°-5° C., and sodium chloride (6.0 Kg) was added. The aqueous solution was extracted with isopropyl acetate (50 L aliquots at 0°-5° C.). The target compound (8.5 Kg) was isolated via crystallization. 

What is claimed is:
 1. A process for the synthesis of an N-(di-substituted phosphoryl)-trans-4-hydroxy-L-proline of the formula I: ##STR10## wherein R¹ and R² independently represent C₁₋₁₈ alkyl, phenyl or phenyl-C₁₋₁₈ alkyl, or R¹ and R² are taken in combination to represent C₂₋₄ alkylidene or phenyl,wherein trans-4-hydroxy-L-proline of the formula II: ##STR11## is reacted within a di-(substituted) phosphite of the formula III: ##STR12## in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula I.
 2. A process in accordance with claim 1 wherein R¹ and R² independently represent C₁₋₁₈ alkyl.
 3. A process in accordance with claim 1 wherein R¹ and R² independently represent phenyl-substituted C₁₋₁₈ alkyl.
 4. A process in accordance with claim 1 wherein R¹ and R² each independently represent phenyl.
 5. A process in accordance with claim 1 wherein R¹ and R² taken in combination represent C₂₋₄ alkylidene or phenyl.
 6. A process in accordance with claim 5 wherein R¹ and R² taken in combination represent ethylene.
 7. A process in accordance with claim 1 wherein R¹ and R² independently or in combination represent members selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl, 2-ethylhexyl, decyl, lauryl, octadecyl and ethylene.
 8. A process for the synthesis of N-(diisopropyl phosphoryl)-trans-4-hydroxy-L-proline of the formula Ia: ##STR13## which comprises reacting trans-4-hydroxy-L-proline of the formula II: ##STR14## with diisopropyl phosphite of the formula IIIa: ##STR15## in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula Ia.
 9. A process in accordance with claim 1 wherein the pH of the reaction is maintained at about 9.0. 